US3911124A - Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors - Google Patents
Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors Download PDFInfo
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- US3911124A US3911124A US437446*A US43744674A US3911124A US 3911124 A US3911124 A US 3911124A US 43744674 A US43744674 A US 43744674A US 3911124 A US3911124 A US 3911124A
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- prostaglandin
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- synthetase inhibitor
- pgb2
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- 230000002496 gastric effect Effects 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims description 40
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 title abstract description 17
- 150000003180 prostaglandins Chemical class 0.000 claims abstract description 51
- 102000003960 Ligases Human genes 0.000 claims abstract description 17
- 108090000364 Ligases Proteins 0.000 claims abstract description 17
- 239000003112 inhibitor Substances 0.000 claims abstract description 17
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims abstract description 16
- 241000124008 Mammalia Species 0.000 claims abstract description 11
- 238000007910 systemic administration Methods 0.000 claims abstract description 10
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960001138 acetylsalicylic acid Drugs 0.000 claims abstract description 8
- 229960000905 indomethacin Drugs 0.000 claims abstract description 8
- 229960002895 phenylbutazone Drugs 0.000 claims abstract description 8
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 claims abstract description 8
- PRFXRIUZNKLRHM-UHFFFAOYSA-N l-prostaglandin B2 Natural products CCCCCC(O)C=CC1=C(CC=CCCCC(O)=O)C(=O)CC1 PRFXRIUZNKLRHM-UHFFFAOYSA-N 0.000 claims abstract 5
- PRFXRIUZNKLRHM-HKVRTXJWSA-N prostaglandin B2 Chemical compound CCCCC[C@H](O)\C=C\C1=C(C\C=C/CCCC(O)=O)C(=O)CC1 PRFXRIUZNKLRHM-HKVRTXJWSA-N 0.000 claims abstract 5
- 230000008569 process Effects 0.000 claims description 35
- 230000006872 improvement Effects 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 10
- 229940094443 oxytocics prostaglandins Drugs 0.000 abstract description 12
- -1 for example Chemical compound 0.000 abstract description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 17
- 239000000126 substance Substances 0.000 description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 241000282412 Homo Species 0.000 description 4
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 4
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 4
- 208000025865 Ulcer Diseases 0.000 description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000007243 oxidative cyclization reaction Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229940114079 arachidonic acid Drugs 0.000 description 2
- 235000021342 arachidonic acid Nutrition 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- MJXYGTJIZMTDND-UHFFFAOYSA-N 2-(2-phenoxyphenyl)propanoic acid Chemical compound OC(=O)C(C)C1=CC=CC=C1OC1=CC=CC=C1 MJXYGTJIZMTDND-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010061459 Gastrointestinal ulcer Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000219061 Rheum Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000013160 medical therapy Methods 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000008288 physiological mechanism Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- WGJJROVFWIXTPA-OALUTQOASA-N prostanoic acid Chemical compound CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O WGJJROVFWIXTPA-OALUTQOASA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 230000001562 ulcerogenic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
Definitions
- this invention relates to an improvement in the process of systemic administration of a prostaglandin synthetase inhibitor to a mammal, said improvement comprising concomitant systemic administration of an amount of a prostaglandin of the PGB-type effective to reduce the undesirable gastrointestinal effects of said prostaglandin synthetase inhibitor.
- Prostaglandin synthetase is a microsomal enzyme complex, which catalyzes the oxidative cyclization of unsaturated C fatty acids, such as arachidonic acid, into prostaglandins (PG) in the presence ofa suitable coenzyme.
- PG prostaglandins
- This oxidative cyclization is presently thought to be an in vivo physiological process initiated by one or more physiological mechanisms of as yet unknown nature.
- prostaglandin synthetase inhibitors are also members of a class known descriptively as non-steroidal anti-inflammatory agents. See, for example, Vane, Nature New Biology, 231, 232 (1971 Takeguchi et al., above cited, and references cited in Takeguchi et al. Included within this class of substances are the well-known antiinflammatory agents indomethacin, aspirin, and phenylbutazone. Others are rnefenamic acid, flufenamic acid, naproxen, 2-phenoxyphenylpropionic acid, (+)3-chloro-4-cyclohexyl-a-methylphenylacetic acid, and ibuprofen.
- Discontinuing administration of the anti-inflammatory agent usually results in alleviation and later substantially complete relief from these undesirable gastrointestinal effects, especially healing of the ulcers. But meanwhile, the patient has no relief from the inflammatory disease for which he was being treated.
- prostaglandins of the PGB-type are useful in reducing the undesirable gastrointestinal effects resulting from systemic administration of anti-inflammatory prostaglandin synthetase inhibitors, and are used for that purpose by concomitant administration of the PGBtype prostaglandin and the anti-inflammatory prostaglandin syn thetase inhibitor.
- This novel process improvement is useful, for example, in reducing the undesirable gastrointestinal effects resulting from systemic administration of indomethacin, phenylbutazone, and aspirin.
- indomethacin, phenylbutazone, and aspirin are substances specifically mentioned in Partridge et al. as non-steroidal antiinflammatory agents. But these are also known to be prostaglandin synthetase inhibitors.
- novel process improvement of this invention is useful only in reducing undesirable gastrointestinal effects caused by antiflammatory agents which are also prostaglandin synthetase inhibitors.
- Undesirable gastrointestinal effects caused by antiflammatory agents which are not prostaglandin synthetase inhibitors are not expected to be reduced by concomitant administration of a PGB-type prostaglandin.
- Prostaglandins may be considered as derivatives of a parent substance known as prostanoic acid, having the following formula and atom numbering:
- a PGB-type prostaglandin is defined as any compound, optically active or racemic, with the structural features above defined and also with 4 to 9 carbon atoms in a chain between the carboxylate function and the ring at (a) and with 4 to 12 carbon atoms in a chain attached to the ring at (b).
- the ring and either chain may have substituents, hetero atoms, and/or carboncarbon double (cis or trans) or triple bonds.
- P68 P63 P68 13, l 4-dihydro PGB, and numerous salts and esters of those are known in the art.
- numerous analogs of PGB PGB P68 and l3,14-dihydro-PGB,, and salts and ester of those are known in the art. See, for example, Pharmacol. Rev. 20, l 1968) and references cited therein. See also U.S. Pat. Nos. 3,069,322; 3,598,858; 3,767,701; 3,767,700; 3,767,697; 3,767,698; 3,759,978; and 3,775,462. See
- any of the known PGB-type free acids, salts, and esters as exemplified in the above-cited publications are useful in the novel process improvement of this invention.
- any PGB-type free acid, salt, or ester which is not toxic at the effective dose and which has the structural features defined above is also useful in the novel process improvement of this invention.
- this invention is an improvement in the administration of anti-inflammatory synthetase inhibitors to mammals and especially to humans.
- the antiinflammatory synthetase inhibitor for example, indo methacin, aspirin, or phenylbutazone is administered in any of the ways known in the art, to alleviate an inflammatory condition, for example, in any dosage regimen and by any of the known routes of systemic administration. It is known, however, that undesirable gastrointes tinal efiects most often result when the route of administration of the anti-inflammatory substance is oral or rectal, and when relatively large amounts of the substance are administered over a prolonged period of time. It is for such routes of administration and for such dosage regimens that the novel improvement which is this invention is most useful.
- the prostaglandin of the PGB-type is administered along with the anti'inflammatory prostaglandin synthetase inhibitor either by the same route of administration or by a different route.
- the PGB-type prostaglandin is also administered orally or, alternatively, is administered rectally in the form of a suppository or, in the case of women, vaginally in the form of a suppository or a vaginal device for slow release, for example, as described in U.S. Pat. No. 3,545,439.
- the PGB-type prostaglandin is also administered rectally or, alternatively, orally or, in the case of women, vaginally. It is especially convenient when the administration route is to be the same for both anti-inflammatory substance and PGB-type prostaglandin, to combine both into a single dosage form.
- Dosage forms for both the anti-inflammatory substance and the PGB-type prostaglandin are prepared by methods known in the art. See, for example, Partridge et al., above cited.
- P013, and P68 are especially preferred. Also especially preferred are PGB, and PGB analogs wherein the molecular structure is the same as in PGB or PGB i.e., formulas V and VI,
- PGB-type prostaglandins to be used according to this invention are the free acid form, the salt form wherein the cation is pharmaceutically acceptable, and the ester fonn wherein the alcohol portion is alkyl, especially alkyl of one to 4 carbon atoms, inclusive, more especially methyl or ethyl.
- the dosage regimen for the PGB-type prostaglandin in accord with this invention will depend upon a variety of factors, including the type, age, weight, sex, and medical condition of the mammal, the nature and dosage regimen of the anti-inflammatory synthetase inhibitor being administered to the mammal, the sensitivity of the particular individual mammal to the particular synthetase inhibitor with regard to gastrointestinal effeels, and the particular PGB-type prostaglandin to be administered. For example, not every human in need of an anti-inflammatory substance experiences the same adverse gastrointestinal effects when taking the substance. The gastrointestinal effects will frequently vary substantially in kind and degree.
- the physician or veterinarian would, of course, start at a relatively low concomitant dose of the PGB-type prostaglandin, for example, about 0.025 mg./kg./day of PGB or about 0.l ug/kg/day of l6,l6-dimethyl-PGB and observe the response of the human or animal patient for a few days. The dose of the PGB-type prostaglandin is then adjusted downward or upward until the minimum effective dose is found.
- the maximum needed dose is usually about 25 mg./kg./day and in the case of 16,16-dimethyl-PGB the maximum needed dose is usually about pg/kg/day, although it may be necessary occasionally to exceed these doses when large amounts of the inflammatory substance are needed for a particular medical indication or when the gastrointestinal response of a particular subject to the anti-inflammatory substance is expecially severe and there is a sound medical reason for maintaining the subject on that particular antiinflammatory substance.
- the minimum effective dose of the particular PCB-type compound is determined for a particular subject, it is advantageous to provide the subject with a single dosage form which contains both the desired amount of the antiinflammatory substance and the amount of the PGB- type prostaglandin effective to obtain the desired gastrointestinal result.
- the term effective amount of the PGB-type substance will mean amounts effective at various time periods during administration of an anti-inflammatory substance.
- An amount of the PGB-type substance effective to allow healing of existing gastrointestinal ulcers, for example, will not necessarily be the same and, indeed, is likely to be more than the amount effective to avoid formation of future ulcers.
- the process improvement which is this invention includes both of these concepts of effective amount.”
Abstract
There is disclosed concomitant systemic administration of prostaglandins of the PGB-type, for example, PGB2, and a prostaglandin synthetase inhibitor, for example, indomethacin, aspirin, or phenylbutazone, to mammals, including humans. Thereby the undesirable gastrointestinal effects of the synthetase inhibitor are reduced.
Description
United States Patent 1 n 1 Robert 1 Oct. 7, 1975 METHOD OF REDUCING THE [56] References Cited UNDESIRABLE GASTROINTESTINAL UNITED STATES PATENTS EFFECTS OF PROSTAGLANDIN 3,781,429 12/1973 Partridge et al. 424/273 SYNTHETASE INHIBITORS Inventor: Andre Robert, Kalamazoo Township, Kalamazoo County, Mich.
Assignee: The Upjohn Company, Kalamazoo,
Mich.
Filed: Jan. 28, 1974 Appl. No.: 437,446
Int.Cl. ..A61K3l/l9;A61K31/6l; A61K3l/215;A6lK3l/415 Field of Search 424/305, 318, 273, 234,
Primary Examiner-Sam Rosen Attorney, Agent, or Firm-Earl C. Spaeth; Bruce Stein 5 7 ABSTRACT 14 Claims, No Drawings METHOD OF REDUCING THE UNDESIRABLE GASTROINTESTINAL EFFECTS OF PROSTAGLANDIN SYNTHETASE INHIBITORS This invention relates to an improvement in a known process of administration of certain medicinal agents to mammals, including humans, to accomplish a desired medicinal result. In particular, this invention relates to an improvement in the process of systemic administration of a prostaglandin synthetase inhibitor to a mammal, said improvement comprising concomitant systemic administration of an amount of a prostaglandin of the PGB-type effective to reduce the undesirable gastrointestinal effects of said prostaglandin synthetase inhibitor.
According to Takeguchi et al., Prostaglandins, 2, 169 (1972), Prostaglandin synthetase is a microsomal enzyme complex, which catalyzes the oxidative cyclization of unsaturated C fatty acids, such as arachidonic acid, into prostaglandins (PG) in the presence ofa suitable coenzyme. See also Nugteren et al., Rec. Trav. Chim. Pays-Bas. 85, 405 (1966); Hamberg et al., J. Biol. Chem. 242, 5336 (1967), and Sih et al., J. Am. Chem. Soc. 92, 6670 1970). This oxidative cyclization is presently thought to be an in vivo physiological process initiated by one or more physiological mechanisms of as yet unknown nature.
1n the case of arachidonic acid (I), this oxidative cyclization is formulated as follows, leading to the prostaglandins known as PGE (II) and/or PGF (III) prostaglandin synthetase It is readily determined in vitro whether or not a particular substance is a prostaglandin synthetase inhibitor. See, for example, Takeguchi et al., above cited.
Many of the substances now known to be prostaglandin synthetase inhibitors are also members of a class known descriptively as non-steroidal anti-inflammatory agents. See, for example, Vane, Nature New Biology, 231, 232 (1971 Takeguchi et al., above cited, and references cited in Takeguchi et al. Included within this class of substances are the well-known antiinflammatory agents indomethacin, aspirin, and phenylbutazone. Others are rnefenamic acid, flufenamic acid, naproxen, 2-phenoxyphenylpropionic acid, (+)3-chloro-4-cyclohexyl-a-methylphenylacetic acid, and ibuprofen.
It is readily determined in vivo whether or not particular substances, including substances known to be prostaglandin synthetase inhibitors, are antiinflammatory agents. See, for example, R. A. Turner, Screening Methods in Pharmacology", Academic Press, New York, Chapter 13, pp. 152-163 (1965), and especially, Winder et al., J. Pharmacol. Exp. Ther. 141, 369 (1963).
It is now well known that administration of certain non-steroidal anti-inflammatory agents, especially by the oral or rectal route, to humans for antiinflammatory purposes often causes undesirable gastrointestinal effects including but not limited to abdominal pain, single or multiple ulcerations, nodules, adhesions, and other types of lesions, bleeding, anorexia, nausea, and the like. See, for example, Boardman et al., Ann. rheum. Dis. 26, 127 (1967); Taylor et al., Brit. Med. J. 4, 734 1968); Fischer et al., Am. J. Gastroent. 51, 42 1969); Sturges et al., Am. J. Gastroent. 59, 162 (1973), Chapman et al., Out, 10, 443 (1909); Smith, Ann. NY. Acad. Sci. 86, 38 (1960); and Gault et al., Ann. Int. Med. 68, 906 (1968). Discontinuing administration of the anti-inflammatory agent usually results in alleviation and later substantially complete relief from these undesirable gastrointestinal effects, especially healing of the ulcers. But meanwhile, the patient has no relief from the inflammatory disease for which he was being treated.
it has been reported that the ulcerogenic effect induced by certain non-steroidal anti-inflammatory agents in rats is inhibited by concomitant oral administration of certain prostaglandins of the E and A series, including PGE PGE PGE l3,l4-dihydro-PGE,, and the corresponding 1 l-deoxy-PGE and PGA compounds. See Partridge et al., US. Pat. No. 3,781,429.
I have now made the surprising discovery that prostaglandins of the PGB-type are useful in reducing the undesirable gastrointestinal effects resulting from systemic administration of anti-inflammatory prostaglandin synthetase inhibitors, and are used for that purpose by concomitant administration of the PGBtype prostaglandin and the anti-inflammatory prostaglandin syn thetase inhibitor. This novel process improvement is useful, for example, in reducing the undesirable gastrointestinal effects resulting from systemic administration of indomethacin, phenylbutazone, and aspirin. These are substances specifically mentioned in Partridge et al. as non-steroidal antiinflammatory agents. But these are also known to be prostaglandin synthetase inhibitors. The novel process improvement of this invention is useful only in reducing undesirable gastrointestinal effects caused by antiflammatory agents which are also prostaglandin synthetase inhibitors. Undesirable gastrointestinal effects caused by antiflammatory agents which are not prostaglandin synthetase inhibitors are not expected to be reduced by concomitant administration of a PGB-type prostaglandin.
Prostaglandins may be considered as derivatives of a parent substance known as prostanoic acid, having the following formula and atom numbering:
x 6 4 2 COOH I 7\/E\/3\/ 1 Q 14 1a 1 1e 1 20 The prostaglandin known as PGB, has the formula:
COOH Prostaglandin E: (PGB has the formula:
Prostaglandin B (PGB has the formula:
VII
13, l 4-Dihydroprostaglandin B, 13, l 4'dihydro-PGB has the formula VIII Thus, it can be seen that PGB-type prostaglandins all have the structural feature:
with a carboxyl-terminated carbon chain attached at carbon atom (a) and a carbon chain attached at carbon atom (b), with an alpha (S) hydroxy on the 3rd carbon atom of the latter chain. For the purposes of this invention, a PGB-type prostaglandin is defined as any compound, optically active or racemic, with the structural features above defined and also with 4 to 9 carbon atoms in a chain between the carboxylate function and the ring at (a) and with 4 to 12 carbon atoms in a chain attached to the ring at (b). The ring and either chain may have substituents, hetero atoms, and/or carboncarbon double (cis or trans) or triple bonds.
P68 P63 P68 13, l 4-dihydro PGB,, and numerous salts and esters of those are known in the art. Moreover, numerous analogs of PGB PGB P68 and l3,14-dihydro-PGB,, and salts and ester of those, are known in the art. See, for example, Pharmacol. Rev. 20, l 1968) and references cited therein. See also U.S. Pat. Nos. 3,069,322; 3,598,858; 3,767,701; 3,767,700; 3,767,697; 3,767,698; 3,759,978; and 3,775,462. See
also German Offenlegungschrift Nos. 2,210,697; 2,036,471; 2,0] 1,969; 2,209,990; 2,154,309; 2,164,184; 2,217,044; 2,221,443; 2,320,368;
2,320,552; 2,322,673; and 2,317,019.
Any of the known PGB-type free acids, salts, and esters as exemplified in the above-cited publications are useful in the novel process improvement of this invention. Moreover, any PGB-type free acid, salt, or ester which is not toxic at the effective dose and which has the structural features defined above is also useful in the novel process improvement of this invention.
The administration to animals and especially to humans of an anti-inflammatory synthetase inhibitor for treatment of inflammation and related physiological condition is not by itself part of this invention. Rather, as discussed above, this invention is an improvement in the administration of anti-inflammatory synthetase inhibitors to mammals and especially to humans.
In order to practice this novel improvement, the antiinflammatory synthetase inhibitor, for example, indo methacin, aspirin, or phenylbutazone is administered in any of the ways known in the art, to alleviate an inflammatory condition, for example, in any dosage regimen and by any of the known routes of systemic administration. It is known, however, that undesirable gastrointes tinal efiects most often result when the route of administration of the anti-inflammatory substance is oral or rectal, and when relatively large amounts of the substance are administered over a prolonged period of time. It is for such routes of administration and for such dosage regimens that the novel improvement which is this invention is most useful.
The prostaglandin of the PGB-type is administered along with the anti'inflammatory prostaglandin synthetase inhibitor either by the same route of administration or by a different route. For example, if the antiinflammatory substance is being administered orally, the PGB-type prostaglandin is also administered orally or, alternatively, is administered rectally in the form of a suppository or, in the case of women, vaginally in the form of a suppository or a vaginal device for slow release, for example, as described in U.S. Pat. No. 3,545,439. Alternatively, if the anti-inflammatory substance is being administered rectally, the PGB-type prostaglandin is also administered rectally or, alternatively, orally or, in the case of women, vaginally. It is especially convenient when the administration route is to be the same for both anti-inflammatory substance and PGB-type prostaglandin, to combine both into a single dosage form.
Dosage forms for both the anti-inflammatory substance and the PGB-type prostaglandin are prepared by methods known in the art. See, for example, Partridge et al., above cited.
Among the PGB'type prostaglandins to be used according to this invention, P013, and P68, are especially preferred. Also especially preferred are PGB, and PGB analogs wherein the molecular structure is the same as in PGB or PGB i.e., formulas V and VI,
above, except that there are one or 2 methyl or ethyl groups at C-l6 rather than hydrogens. These are known analogs of PG and PGB See, for example, German Offenlegungschrift Nos. 2,210,697 and 2,217,044.
Also preferred among the PGB-type prostaglandins to be used according to this invention are the free acid form, the salt form wherein the cation is pharmaceutically acceptable, and the ester fonn wherein the alcohol portion is alkyl, especially alkyl of one to 4 carbon atoms, inclusive, more especially methyl or ethyl.
The dosage regimen for the PGB-type prostaglandin in accord with this invention will depend upon a variety of factors, including the type, age, weight, sex, and medical condition of the mammal, the nature and dosage regimen of the anti-inflammatory synthetase inhibitor being administered to the mammal, the sensitivity of the particular individual mammal to the particular synthetase inhibitor with regard to gastrointestinal effeels, and the particular PGB-type prostaglandin to be administered. For example, not every human in need of an anti-inflammatory substance experiences the same adverse gastrointestinal effects when taking the substance. The gastrointestinal effects will frequently vary substantially in kind and degree. But it is within the skill of the attending physician or veterinarian to determine that administration of the anti-inflammatory substance is causing undesirable gastrointestinal effects in the human or animal subject, and to prescribe an effective amount of the PGB-type prostaglandin to reduce and then substantially to eliminate those undesirable effects. In doing that, the physician or veterinarian would, of course, start at a relatively low concomitant dose of the PGB-type prostaglandin, for example, about 0.025 mg./kg./day of PGB or about 0.l ug/kg/day of l6,l6-dimethyl-PGB and observe the response of the human or animal patient for a few days. The dose of the PGB-type prostaglandin is then adjusted downward or upward until the minimum effective dose is found. For example, in the case of P68 the maximum needed dose is usually about 25 mg./kg./day and in the case of 16,16-dimethyl-PGB the maximum needed dose is usually about pg/kg/day, although it may be necessary occasionally to exceed these doses when large amounts of the inflammatory substance are needed for a particular medical indication or when the gastrointestinal response of a particular subject to the anti-inflammatory substance is expecially severe and there is a sound medical reason for maintaining the subject on that particular antiinflammatory substance. Once the minimum effective dose of the particular PCB-type compound is determined for a particular subject, it is advantageous to provide the subject with a single dosage form which contains both the desired amount of the antiinflammatory substance and the amount of the PGB- type prostaglandin effective to obtain the desired gastrointestinal result.
Since not all animal and human subjects have adverse gastrointestinal responses to administration of an antiinflammatory prostaglandin synthetase inhibitor, rational medical therapy indicates that the PGB-type compound not be administered until the need for that appears in any particular animal or human subject. But when this need is observed, it can be expected that, at least in some subjects, a higher dose level of the P- type compound will be needed along with the antiinflammatory substance to allow the gastrointestinal tract to return to normal during continued administration of the anti-inflammatory substance than will later be necessary to maintain a normal gastrointestinal tract. It is, however, within the skill of the attending physician or veterinarian to adjust the dose of the P68- type substance to meet the needs of the individual human or animal subject especially in the usual situations involving long term regimens of antiinflammatory substances. In this respect, the term effective amount of the PGB-type substance will mean amounts effective at various time periods during administration of an anti-inflammatory substance. An amount of the PGB-type substance effective to allow healing of existing gastrointestinal ulcers, for example, will not necessarily be the same and, indeed, is likely to be more than the amount effective to avoid formation of future ulcers. The process improvement which is this invention includes both of these concepts of effective amount."
I claim:
1. In the process of systemic administration of an anti-inflammatory prostaglandin synthetase inhibitor to a mammal, the improvement which comprises concomitant systemic administration of an amount of a prostaglandin of the PGB-type effective to reduce the undesirable gastrointestinal effects of said prostaglandin synthetase inhibitor.
2. The process of claim 1 wherein the mammal is a human.
3. The process of claim 2 wherein the synthetase inhibitor is administered orally or rectally, and the prostaglandin is administered orally, rectally, or, in the case of a woman, vaginally.
4. The process of claim 2 wherein the synthetase inhibitor and the prostaglandin are both administered orally.
5. The process of claim 3 wherein the synthetase inhibitor is indomethacin, aspirin, or phenylbutazone.
6. The process of claim 4 wherein the synthetase inhibitor is indomethacin, aspirin, or phenylbutazone.
7. The process of claim 3 wherein the prostaglandin is of the PGB -type.
8. The process of claim 4 wherein the prostaglandin is of the PGB -type.
9. The process of claim 5 wherein the prostaglandin is of the PGB -type.
10. The process of claim 6 wherein the prostaglandin is of the PGB -type.
1 l. The process of claim 3 wherein the prostaglandin is PGB, or a pharrnaceutically acceptable salt thereof.
12. The process of claim 4 wherein the prostaglandin is P68 or a pharmaceutically acceptable salt thereof.
13. The process of claim 5 wherein the prostaglandin is PGB or a pharmaceutically acceptable salt thereof.
14. The process of claim 6 wherein the prostaglandin is PS8, or a pharmaceutically acceptable salt thereof. =l m
Claims (14)
1. IN THE PROCESS OF SYSTEMIC ADMINISTRATION OF AN ANTI-INFLAMMATORY PROSTAGLADIN SYNTHETASE INHIBITOR TO A MAMMAL THE IMPROVEMENT WHICH COMPRISES CONCOMITANT SYSTEMIC ADMINISTRATION OF AN AMOUNT OF A POROSTAGLADIN OF THE PGB-TYPE EFFECTIVE TO REDUCE THE UNDESIRABLE GASTROINTESTINAL EFFECTS OF SAID PROSTAGLADIN SYNTHETASE INHIBITOR.
2. The process of claim 1 wherein the mammal is a human.
3. The process of claim 2 wherein the synthetase inhibitor is administered orally or rectally, and the prostaglandin is administered orally, rectally, or, in the case of a woman, vaginally.
4. The process of claim 2 wherein the synthetase inhibitor and the prostaglandin are both administered orally.
5. The process of claim 3 wherein the synthetase inhibitor is indomethacin, aspirin, or phenylbutazone.
6. The process of claim 4 wherein the synthetase inhibitor is indomethacin, aspirin, or phenylbutazone.
7. The process of claim 3 wherein the prostaglandin is of the PGB2-type.
8. The process of claim 4 wherein the prostaglandin is of the PGB2-type.
9. The process of claim 5 wherein the prostaglandin is of the PGB2-type.
10. The process of claim 6 wherein the prostaglandin is of the PGB2-type.
11. The process of claim 3 wherein the prostaglandin is PGB2 or a pharmaceutically acceptable salt thereof.
12. The process of claim 4 wherein the prostaglandin is PGB2 or a pharmaceutically acceptable salt thereof.
13. The process of claim 5 wherein the prostaglandin is PGB2 or a pharmaceutically acceptable salt thereof.
14. The process of claim 6 wherein the prostaglandin is PGB2 or a pharmaceutically acceptable salt thereof.
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US437446*A US3911124A (en) | 1974-01-28 | 1974-01-28 | Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors |
ZA00748214A ZA748214B (en) | 1974-01-28 | 1974-12-30 | Medical treatment with prostaglandins |
AU77011/74A AU489196B2 (en) | 1974-12-31 | n PROCESS of SYSTEMIC ADMINISTRATION OFA PROSTAGLANDIN SYNTHETASE INHIBITOR TOA MAMMAL | |
GB362575A GB1463955A (en) | 1974-01-28 | 1975-01-28 | Compositions containing prostaglandins |
BE152773A BE824858A (en) | 1974-01-28 | 1975-01-28 | ANTI-INFLAMMATORY COMPOSITIONS AND THEIR USE |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US437446*A US3911124A (en) | 1974-01-28 | 1974-01-28 | Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
US3911124A true US3911124A (en) | 1975-10-07 |
Family
ID=23736486
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US437446*A Expired - Lifetime US3911124A (en) | 1974-01-28 | 1974-01-28 | Method of reducing the undesirable gastrointestinal effects of prostaglandin synthetase inhibitors |
Country Status (4)
Country | Link |
---|---|
US (1) | US3911124A (en) |
BE (1) | BE824858A (en) |
GB (1) | GB1463955A (en) |
ZA (1) | ZA748214B (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4083998A (en) * | 1976-02-17 | 1978-04-11 | The Upjohn Company | Treatment of inflammatory diseases of the mammalian large intestine with cytoprotective prostaglandins |
EP1005336A1 (en) * | 1997-07-09 | 2000-06-07 | Androsolutions, Inc. | Improved methods and compositions for treating male erectile dysfunction |
US6410595B1 (en) | 1997-07-09 | 2002-06-25 | Androsolutions, Inc. | Methods and compositions for treating male erectile dysfunction |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2135881A (en) * | 1983-03-02 | 1984-09-12 | Erba Farmitalia | Method and pharmaceutical compositions for inhibiting or reducing gastrointestinal side effects of non-steroidal anti-inflammatory drugs |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3781429A (en) * | 1972-09-29 | 1973-12-25 | American Cyanamid Co | Method of inhibiting ulcerogenesis induced by non-steroidal anti-inflammatory agents |
-
1974
- 1974-01-28 US US437446*A patent/US3911124A/en not_active Expired - Lifetime
- 1974-12-30 ZA ZA00748214A patent/ZA748214B/en unknown
-
1975
- 1975-01-28 BE BE152773A patent/BE824858A/en not_active IP Right Cessation
- 1975-01-28 GB GB362575A patent/GB1463955A/en not_active Expired
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3781429A (en) * | 1972-09-29 | 1973-12-25 | American Cyanamid Co | Method of inhibiting ulcerogenesis induced by non-steroidal anti-inflammatory agents |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4083998A (en) * | 1976-02-17 | 1978-04-11 | The Upjohn Company | Treatment of inflammatory diseases of the mammalian large intestine with cytoprotective prostaglandins |
EP1005336A1 (en) * | 1997-07-09 | 2000-06-07 | Androsolutions, Inc. | Improved methods and compositions for treating male erectile dysfunction |
EP1005336A4 (en) * | 1997-07-09 | 2001-01-17 | Androsolutions Inc | Improved methods and compositions for treating male erectile dysfunction |
US6410595B1 (en) | 1997-07-09 | 2002-06-25 | Androsolutions, Inc. | Methods and compositions for treating male erectile dysfunction |
US6414027B1 (en) | 1997-07-09 | 2002-07-02 | Androsolutions, Inc. | Methods and compositions for treating male erectile dysfunction |
US6559184B2 (en) | 1997-07-09 | 2003-05-06 | Androsolutions, Inc. | Methods and compositions for treating male erectile dysfunction |
Also Published As
Publication number | Publication date |
---|---|
GB1463955A (en) | 1977-02-09 |
BE824858A (en) | 1975-07-28 |
ZA748214B (en) | 1976-01-28 |
AU7701174A (en) | 1976-07-01 |
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